PSMA PET Imaging in Clinical Practice - Thomas Hope & Jeremie Calais

January 3, 2023

Matthew Cooperberg is joined by Tom Hope and Jeremie Calais in a discussion PSMA PET agents that have been approved by the US Food and Drug Administration (FDA) and their effect on clinical practice. Positron Emission Tomography (PET) nuclear imaging technique is used to detect prostate cancer. Combining PET with Prostate Specific Membrane Antigen (PSMA) helps doctors to specifically identify prostate cancer. For the past few decades, researchers have continued to study how they can use PSMA-targeted radiolabeled constructs to track the progression of the disease and how a person is responding to treatment. Drs. Cooperberg, Hope, and Calais review the most recent advances including 68-Ga-PSMA-11, 18-F-DCFPyL, and the kit for the preparation of the gallium Ga 68 injection. They also take into consideration the March 2022 FDA approval of Lutetium PSMA [177Lu]Lu-PSMA-617 (PluvictoTM). The current availability of PSMA PET agents has made it easier for researchers to include them in their clinical trials. Drs. Hope, Calais, and Cooperberg look forward to data-driven management coming out of our learnings from these clinical trials. 

Biographies:

Jeremie Calais, MD, MsC, Associate Professor, Nuclear Medicine and Theranostics, Director, Clinical Research Program of the Ahmanson Translational Theranostics Division, University of California, Los Angeles

Thomas Hope, MD, Associate Professor, Vice Chair of Clinical Operations and Strategy in the Department of Radiology, Director of Molecular Therapy, Chief of Nuclear Medicine at the San Francisco VA Medical Center and chair of the Cancer Center’s Molecular Imaging & Radionuclide Therapy Site Committee.

Matthew Cooperberg, MD, MPH, FACS, Professor of Urology; Epidemiology & Biostatistics, Helen Diller Family Chair in Urology, The University of California, San Francisco, UCSF


Read the Full Video Transcript

Matt Cooperberg: Hi, I'm Matt Cooperberg. Welcome to another installment of the UroToday Clinically Localized Prostate Cancer Center of Excellence interviews, live at ASCO, 2022. It is my pleasure today to be joined by what can only be described as the dream team for PSMA Imaging, Tom Hope from UCSF and Jeremie Calais from UCLA. I think the two people who really deserve the most credit for bringing PSMA to clinical practice in the United States. So welcome both of you.

Jeremie Calais: Thank you for having me. And good to do that with you, Tom.

Tom Hope: Yeah. I haven't seen Jeremie since pre-COVID. Can you believe that?

Matt Cooperberg: It's great, all, to be breathing the same air. So obviously very busy year for PSMA. I think maybe where we'll start is just what do you guys both think the highlights are of what we've seen happen over the last year or so? Both what's being presented at the meeting here, but also in general.

Jeremie Calais: That's a pretty broad topic.

Matt Cooperberg: It is.

Jeremie Calais: PSMA is booming since... For at least five years. But then we've seen the approval, by the FDA, of multiple PSMA PET agents in the last year. There was PSMA 11 first, then DCFPYL, then the kit to do gallium PSMA-11. So it's getting more and more widely available. And then that's for the imaging part. And then just recently there was the approval of Lutetium PSMA,  the therapy portion. So it is coming and it's getting real here in the US. And on the side of that you have all the questions that go with it and for which the research is trying to answer. Maybe we can talk about that.

Tom Hope: Yeah, for me, I think the interesting thing is how I'm hoping soon PSMA becomes boring. Years ago I used to talk about when, the day when we no longer have to do multiple imaging studies stage prostate cancer patients. And that day's passed. Being able to do PSMA PETs dime a dozen now. Centers around the country are doing it and it's standard clinical practice and it's sort of crazy to be involved in a process where the way we do stage patients in prostate cancer has just completely been transformed in about a two year period. So it's sort of fun to watch it actually happen.

Matt Cooperberg: So that pace has actually introduced its own challenges, right? Because we have completely changed, as you say, how we stage prostate cancer, but we have a whole body of evidence for 20 years based on older staging. So where do you think we are with using the information to make decisions that, especially focusing on localized disease, either before or after primary treatment, do we have the information we need? And if not, what trials do we need to be thinking about to answer the questions of "What do we do with the results?"

Tom Hope: I think one thing that's important to realize is people always talk about... Trials were done with older imaging studies; that does not mean that you should image patients with older imaging modalities now, when we have something better. Just because data based on less sensitive imaging doesn't mean we should go back to that in patients. So we should still move forward with PSMA PET. Now how we use that, we have to be intelligent about it; and there's clearly a migration in the way patients are being managed that's not data driven at the moment and in essence, every single clinical setting needs a clinical trial to understand how to redefine the patient population and the appropriate therapy. And maybe Jeremie can talk about the work you're doing in this space.

Jeremie Calais: Yeah, I want to add on that. I think now that all the PSMA PET agents are more and more available and FDA approved, there will be, I think, more easiness to implement them into clinical trials. Before, it was a challenge to implement both investigational imaging technique within a clinical trial that is coming. So now at least this one is approved and you can implement it in clinical trial. And later in a few years maybe we can have major data.... To really have data driven management. For now, it is not data driven, it is more, let's say, "common sense of the clinicians" to act on it. And clearly there is stage migration and I think the future trial will tell us how exactly we can use PSMA PET at best for the best outcome.

Matt Cooperberg: What do you think we do from the common sense standpoint? The one, maybe, counter example or counter question in terms of traditional imaging is it's all question of defining oligometastatic disease. Of course, we've talked about this before, but we've got tons of trials now really based on bifurcating between oligo and poly metastatic disease. And I think the question still comes up if you see a half a dozen or eight or nine lesions on a PSMA scan and that were only two lesions on a bone scan, do we consider that patient oligometastatic or not? And I think there is still a subset of people out there that will get a bone scan after the PSMA just to try to decide whether or not we're bucketing that patient as oligo. Do you think we'll get to a point where we don't need to do that, short of redoing these trials?

Jeremie Calais: We're actually doing a study at UCLA where we prospectively compare patient that are CRPC bone scan and PSMA. What we find is that there is no real superiority in terms of findings. PSMA may have show a little bit more lesions, but at the end, for now we are at 20% of recruitment. It's more like non-superiority or equality. So it means you don't need to do the bone scan. PSMA PET gives you the information in the bone and in the soft tissue at the same time.

Now there is the stage migration. PSMA PET is the most sensitive imaging technique that we can do, but it's not perfect when you see three lesion on the PSMA PET, it doesn't mean you have no macrometastasis somewhere else in the body. It's just that you underestimate less compared to before the burden of the disease. So in my experience, all oligometastatic-targeted approach for therapy, they work well when there is one or maybe two lesions on PSMA PET, and the threshold is three or five, in my experience, is already too much. When it's four or five lesion, usually it's already poly [inaudible 00:05:59].

Matt Cooperberg: What about your thoughts?

Tom Hope: Well, I think the low verse high volume question, that's usually where it comes up; in the old CHAARTED environment. And we were okay there for a minute, right? Because then abiraterone was approved in castration-sensitive in low and high volume, and we just stopped using docetaxel for a period of time and now we're back... We're throwing chemo back in. And so now it becomes an issue once again. So people use chemo I think less... So it's not like someone counted four bone lesions and would add chemo and if it was three you wouldn't give chemo. It really was more of a high volume setting. And I think clinicians are usually pretty erudite about how to use chemo in the upfront setting.

So I'm hoping most people won't get a bone scan to tell that. But I mean sure there are people who will do it. And I also hope that no one reruns that trial because there's going to be the next... There's PSMAdditon that's going to be coming out soon enough and that will be adding another layer. I guess we'll have to have a abiraterone, docetaxel, plus PSMA-617 trial someday. So we can just do all of the available therapies simultaneously in patients.

Matt Cooperberg: Interesting. So as we have approval of these new agents and new kits now, what's your sense of the promulgation of the technology into the community? In other words, what's your sense of how access is, both in terms of breadth of access and equity of access; and the related question, are there concerns about the quality of the reads in the community? In standardization and... What work has to be done there?

Jeremie Calais: You go?

Tom Hope: Okay, so breadth of access. I think one of the things I'm proud of, and maybe Jeremie is as well, is when we got PSMA-11 proved as generic. We didn't patent it, we couldn't have patented it, but we didn't pay for exclusivity when we registered with the FDA. And so through that there's now two kits available from Telix and Novartis, and there's also DCFPyL or Piflufolastat. And so there's three PET Radiopharmaceuticals out there that are being distributed. And I do think that the availability of the kits is a big impact on availability because PET Radiopharmaceutical distribution networks aren't everywhere in the country and so even fluciclovine was around for a long period of time; there were still access issues.

But Telix, with the kits, in order to sell has to go to places where DCFPyL is not as available, right? So just by the way the market works, there's actually going to be quite a lot of availability because of these two competing companies trying to just obtain market access. So I think over the next year you'll pretty much find most everywhere having, not everywhere, but a very high percentage of the US having availability. In terms of the technique-

Jeremie Calais: There are other PSMA PET agents that are on their way to be approved, too. I mean, I guess they would be approved. So it'll bring even more company on the markets that will have to compete; and the access will be a key point for them to survive. I think giving access to more people or two.

Matt Cooperberg: Any reasons to, all things being equal, to use the kit versus PyL?

Jeremie Calais: No, it's just a way to get the PET radionuclide onto the PSMA and then there are just multiple methods and so people will try to sell different methods.

Matt Cooperberg: And what about this question of standardization? What's your sense of... The quality of reads that you're seeing done in the community? False-positives? Is there... And how close are we to reliable standardization?

Tom Hope: Go for it.

Jeremie Calais: Yeah, there is a clear learning curve, that with any medical technique, any imaging technique, you have to learn how to use it; at best, know what are the limitation, the pro and cons and whether it performs well or not. So clearly there's a learning curve. Me as a PET imaging reader compared to other prior PETs imaging tracer I have worked with, it is still considered easier to other; because the tumor to background ratio... The contrast of the images is much higher due to the PSMA over expression. For [inaudible 00:10:06], choline, FDG, sometime you're always in these borderline cases where you cannot really make a difference. You still have that in PSMA, just less. And then it's on the learning curve of communication between the referring physician, the neurologist, the medical oncologist, the radiation oncologist, and the radiologist or nuclear medicine physician, who have to learn how to communicate on... Give the best information for each patient.

And I think it's really on both sides. There is the nuclear medicine physician who needs to learn all the prostate cancer disease stage, the patient journey, "what does it mean?"; all the prostate cancer usual parameters. And there is, on the clinician side, understand what is SUV, what is low intimidate uptake, "what are the tricky ones?" That there is a learning curve but I think we're getting there. We had seen such a rapid uptake of the clinician at UCLA after one or two years, every patient just go to PSMA PET scan. So from all the medical oncologists, radiation oncologists, zoologists. So I think it highlights very well how it become indispensable for all the prostate cancer management.

Matt Cooperberg: How often you find, I know you both get a lot of requests for over-reads and rereads, how often... Do you find that the frequency where you're coming up with a different interpretation than the original read is improving? Is decreasing? Or has that been fairly stable so far?

Tom Hope: Okay, I would say so. There's definitely a learning curve as when we read these. And Jeremie, I think describe that really well. I don't think we've been around long enough to see it decrease dramatically in the community. We get asked to review cases that are the marginal ones and usually there's not a right answer most of the time. And I think the thing that's really unique about PSMA and prostate cancer for us in nuclear medicine is one single little node has a huge impact in the journey of that patient. But most other diseases, one single little node doesn't dramatically impact the outcome or the management of that patient. So a lot of things can hinge on a borderline rib lesion, right? If you think that's really a disease, patients don't get surgery, they don't get potentially curative radiation therapy.

So you really have to think very differently about calling disease in different settings in prostate cancer than you would with other types of cancer. So I think a lot of nuclear medicines need to learn what matters. When you say something, is that going to have a huge impact? And you want to be really sure because you could potentially be altering for the negative... The management of a patient if you're not interpreting it correctly.

Matt Cooperberg: Maybe shift gears a little bit. Both institutions have these nascent programs in intraoperative localization. Maybe tell us a little bit about what UCLA is doing with gamma probe.

Jeremie Calais: Yeah. We can use PSMA, this protein target for multiple purposes. We can send a tracer to do PET imaging and take into advantage the over-expression for detection. We can use it to deliver a better radiation therapy with potassium, but we can also send a gamma emitting radionuclides. And so gamma is the one that you use to do bone scan, to do conventional sensography. And that's also very easily detectable with intra-operative probe. So for the surgeon that's for example, techniques that are used for sentinel lymph node dissections. Here you would inject, intravenously, the Technetium, which is a gamma emitter, allowing PSMA, to go to the PSMA targets; circulate through the body. Usually you wait about 15 to 20 hours. Let the background decrease, and you still have enough half-life and activity to be able to detect it the day after. Patient goes to surgery, and the surgeon will use a gamma intra-operative probe to detect difficult cases of lymph node. So, that's the principle.

What is the indication of that? The indication is, in patient with very limited amount of lymph node disease because otherwise it's just too late, there would be too many to go. Where there might be an interest to chase maybe one or two lesions and maybe improve the outcome because maybe that's just the whole burden of the disease, maybe. And maybe they're so small, but because PSMA PET can show a very small lesions that just surgically, technically to be visual and to be able to get them for the surgeon is very difficult. So here you use the radio activity to help to guide the surgeon. And we had already a couple of nice stories with Dr. Reiter at UCLA. It's a great collaborative project, multidisciplinary. For me, it's very enjoyable. I go to the OR, we help with the physicists, to make the probe working, to show the images. And sometime you in the void of the peri-rectal fat or somewhere and for the surgeon and you're chasing for discounts.

And we got them, sometime two millimeter node that was otherwise impossible to detect. Now whether this is really improving outcome, this will follow later, but at least technically it is visible and it's another way to use with radioactive molecules, the PSMA over expression in prostate cancer for another purpose.

Matt Cooperberg: Actually one follow up question is, do you think this will be valuable for margin detection as well?

Jeremie Calais: So that's the ultimate goal. For example, Dr. Reiter, when he came to us, "Okay guys, you have PSMA PET. That's good now, but I've seen we can do that. Let's do it for.." So he initiate the ideas and we work together to provide our colleagues with the Radiopharmaceutical new advancement. And the initial idea was to do that for the residual margin. There are many challenges. I think the residual margin are too small, it's too microscopic. What we're looking at in chasing will be too difficult to detect with the current gamma probe. There will be too much background. So I think it's still challenging. You will need a very specific probe. People are working on that, though. But if I have to choose an approach for this indication, I think I would go for a few reasons, targeted with PSMA.

Matt Cooperberg: And last question is an open ended one, actually two part; for each of you, what do you think is the most exciting development happening now in imaging, PSMA based? And if you had to choose one trial or one future direction, what would that be? What's the most important question we can be asking right now? It can be more than one. What are you most excited about?

Tom Hope: So I'd say what I'm not excited about, how about that?

Matt Cooperberg: We can start there.

Tom Hope: So I don't think the next generation PSMA PET Radiopharmaceuticals... There's multiple trials with new agents. They're not going to change anything. It's going to make availability... They're coming down the pipe, but that doesn't impact anything. I think of them as a class interchangeable. And I haven't seen anything from a PSMA PET imaging standpoint that would impact patient outcomes. So the trials are not imaging trials. They're how imaging impacts outcome. And I think in that setting, there's a bunch... I mean there's a whole number of these trials and Jeremie has a wonderful trial that's completed an enrollment of using randomized patients to conventional imaging to PSMA PET and really trying to understand how we manage patients with PSMA PET. But I don't think the next set of imaging trials are actually particularly exciting on how it's going to impact prostate cancer.

Matt Cooperberg: All right.

Jeremie Calais: I do think there are still some things to do with PSMA PET imaging that can be exciting. It would not be a game changer; see that we something we never saw before. But I think integrating PSMA PET, as you just say, into the treatment guidelines, see again.... Refining the treatment algorithms. This we will still learn in the future. I think there are two main things I see as an imaging nuclear medicine physician doctor that can be interesting is therapy response assessment; come up with criteria and how to use PSMA PET as a early endpoint tool rather than, I don't know PSA or other imaging based criteria. That can be very helpful to harvest much of data from clinical trials much faster. And I look forward to that. We come up with some criteria. There are people are working on that. And I also think that the PET imaging is a whole body imaging modality.

So in the advanced population, patient with a lot of disease; here, one of the key parameter you can extract from these images, is the whole body quantitative parameter. The volume, and the intensity of take as assessed by SUV Mean. And there are multiple vendors, multiple academic researchers that try to implement automatic or semiautomatic algorithms to compute this volume and this SUV and this... I'm sure once they will be very widely and consistently available, we will have two new parameters, which are whole body volume, PSMA, whole body PSMA, SUV Mean and these have extremely high predictive and prognostic value for various applications. And this, we will use it again for various treatment, and I'm sure this will be very... Especially for systemic therapy selection or response assessment, that can be very impactful.

Matt Cooperberg: Thank you very much for your time. Yeah, and we'll wrap up.

Tom Hope: Thanks.
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